Cannabinoid receptor 2 agonist AM1241 alleviates epileptic seizures and epilepsy-associated depression via inhibiting neuroinflammation in a pilocarpine-induced chronic epilepsy mouse model.

Increasing evidence suggests that cannabinoid receptor 2 (CB2R) serves as a promising anti-inflammatory target. While inflammation is known to play crucial roles in the pathogenesis of epilepsy, the involvement of CB2R in epilepsy remains unclear. This study aimed to investigate the effects of a CB2R agonist, AM1241, on epileptic seizures and depressive-like behaviors in a mouse model of chronic epilepsy induced by pilocarpine. A chronic epilepsy mouse model was established by intraperitoneal administration of pilocarpine. The endogenous cannabinoid system (eCBs) in the hippocampus was examined after status epilepticus (SE). Animals were then treated with AM1241 and compared with a vehicle-treated control group. Additionally, the role of the AMPK/NLRP3 signaling pathway was explored using the selective AMPK inhibitor dorsomorphin. Following SE, CB2R expression increased significantly in hippocampal microglia. Administration of AM1241 significantly reduced seizure frequency, immobility time in the tail suspension test, and neuronal loss in the hippocampus. In addition, AM1241 treatment attenuated microglial activation, inhibited pro-inflammatory polarization of microglia, and suppressed NLRP3 inflammasome activation in the hippocampus after SE. Further, the therapeutic effects of AM1241 were abolished by the AMPK inhibitor dorsomorphin. Our findings suggest that CB2R agonist AM1241 may alleviate epileptic seizures and its associated depression by inhibiting neuroinflammation through the AMPK/NLRP3 signaling pathway. These results provide insight into a novel therapeutic approach for epilepsy.

Impact of central-line-associated bloodstream infections and catheter-related bloodstream infections: a systematic review and meta-analysis.

OBJECTIVE: Accurate effect estimates are needed to inform input parameters of health economic models. Central-line-associated bloodstream infections (CLABSIs) and catheter-related bloodstream infections (CRBSIs) are different definitions used for central-line bloodstream infections and may represent dissimilar patients, but previous meta-analyses did not differentiate between CLABSIs/CRBSIs. In this meta-analysis, we provided outcome effect estimates in CLABSI and CRBSI patients, compared to uninfected patients. METHODS: We searched PubMed, EMBASE and CINAHL from January 2000 to March 2024 for full-text studies reporting all-cause mortality and/or hospital length of stay (LOS) in adult inpatients with and without CLABSI/CRBSI. Two investigators independently reviewed all potentially relevant studies and performed data extraction. Odds ratio for mortality and mean difference in LOS were pooled using random-effects models. Risk of study bias was assessed using ROBINS-E. RESULTS: We included 36 studies. Sixteen CLABSI and 12 CRBSI studies reported mortality. The mortality odds ratios of CLABSIs and CRBSIs, compared to uninfected patients, were 3.19 (95% CI, 2.44, 4.16, I2=49%) and 2.47 (95% CI, 1.51, 4.02, I2=82%) respectively. Twelve CLABSI and eight CRBSI studies reported hospital LOS; only three CLABSI studies and two CRBSI studies accounted for the time-dependent nature of CLABSIs/CRBSIs. The mean differences in LOS for CLABSIs and CRBSIs compared to uninfected patients were 16.14 days (95% CI, 9.27, 23.01, I2=91%) and 16.26 days (95% CI, 10.19, 22.33, I2=66%) respectively. CONCLUSION: CLABSIs and CRBSIs increase mortality risk and hospital LOSs. Few published studies accounted for the time-dependent nature of CLABSIs/CRBSIs, which can result in overestimation of excess hospital LOS.

Ironing out Persisters? Revisiting the Iron Chelation Strategy to Target Planktonic Bacterial Persisters Harboured in Carbapenem-Resistant Escherichia coli.

Antibiotic resistance is a global health crisis. Notably, carbapenem-resistant Enterobacterales (CRE) pose a significant clinical challenge due to the limited effective treatment options. This problem is exacerbated by persisters that develop upon antibiotic exposure. Bacteria persisters can tolerate high antibiotic doses and can cause recalcitrant infections, potentially developing further antibiotic resistance. Iron is a critical micronutrient for survival. We aimed to evaluate the utility of iron chelators, alone and in combination with antibiotics, in managing persisters. We hypothesized that iron chelators eradicate CRE persisters in vitro, when administered in combination with antibiotics. Our screening revealed three clinical isolates with bacteria persisters that resuscitated upon antibiotic removal. These isolates were treated with both meropenem and an iron chelator (deferoxamine mesylate, deferiprone or dexrazoxane) over 24 h. Against our hypothesis, bacteria persisters survived and resuscitated upon withdrawing both the antibiotic and iron chelator. Pursuing our aim, we next hypothesized that iron chelation is feasible as a post-antibiotic treatment in managing and suppressing persisters' resuscitation. We exposed bacteria persisters to an iron chelator without antibiotics. Flow cytometric assessments revealed that iron chelators are inconsistent in suppressing persister resuscitation. Collectively, these results suggest that the iron chelation strategy may not be useful as an antibiotic adjunct to target planktonic bacteria persisters.